Mesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients

Xinran Yuan,Wanjun Chen,Xiaodong Qin,Zhuoya Zhang,Dandan Wang,Xiaojun Tang,Xiang Gao,Lingyun Sun

doi:10.1038/s41467-019-10491-8

Abstract

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.

Highlights

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood
The number of CD1c+dendritic cells (DCs) in SLE patients was markedly decreased compared to healthy controls (HC) (Fig. 1b, c, d) and patients with rheumatoid arthritis (RA) (Supplementary Fig. 1)
The mechanisms that account for umbilical cord-derived MSCs (UC-MSCs)-mediated immunoregulation in lupus patients remain incompletely understood

Summary

Introduction

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. We show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. In response to Escherichia coli (E.coli) stimulation, human peripheral CD1c+DCs produced only low levels of tumor necrosis factor (TNF), IL-6, IL-12. Instead, they produced high levels of the antiinflammatory cytokine IL-10 and regulatory molecules indoleamine 2,3-dioxygenase (IDO). Previous studies have reported the abnormalities of DCs in SLE, the number and function of tolerogenic CD1c+DC subset in lupus patients remain largely unknown

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